tbuckley/cabot-search huggingface dataset:
NCOG-10. SURGERY FOR RECURRENT GBM: A RETROSPECTIVE CASE-CONTROL STUDY
Authors: Mathew Voisin, Jeffrey Zuccato, Justin Wang, Gelareh Zadeh
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE The role of surgery in recurrent GBM remains a controversial topic. The goal of this study was to perform a case-control analysis including time to tumor recurrence as an additional prognostic factor in order to determine which patients benefit most from repeat surgery. METHODS Our brain tumor database was reviewed over a ten-year period for all adult (≥ 18 years old) patients with primary IDH wildtype GBM that received surgery for recurrent disease. These patients were then age, sex, and treatment-matched to case-controls from our institution that received medical therapy for recurrent disease. RESULTS A total of 174 adult patients with GBM were included in the study, 87 patients that received surgery for recurrent GBM (surgery cohort) and 87 patients that did not receive surgery for recurrent GBM (non-surgery cohort). The surgery cohort had longer overall survival (p = 0.0003) and post recurrence survival (p = 0.001) than the non-surgery cohort. When the surgery cohort was split into two groups based on time to tumor recurrence, the long time to recurrence group ( &amp;gt; 6 months) demonstrated significantly increased survival compared to the short time to recurrence group (p &amp;lt; 0.0001). Multivariate analysis of both cohorts demonstrated surgery for recurrent GBM was independently significant after adjusting for age, KPS, and time to tumor recurrence (p &amp;lt; 0.0001). CONCLUSIONS Surgery for recurrent GBM leads to improved survival independent of age, KPS, and time to tumor recurrence. Patients with time to tumor recurrence greater than 6 months benefit most from additional surgery.
NIMG-87. CHARACTERIZING IMMUNE PROFILES OF PEDIATRIC MEDULLOBLASTOMA AND THEIR RADIOLOGICAL CORRELATES
Authors: Ariana Familiar, Chao Zhao, Meen Chul Kim, Nastaran Khalili, Rachel Madhogarhia, Sherjeel Arif, Sina Bagheri, Hannah Anderson, Debanjan Haldar, Jeffrey B Ware, Arastoo Vossough, Philip B Storm, Adam C Resnick, Anahita Fathi Kazerooni, Ali Nabavizadeh
Journal: Neuro-Oncology (2022)

Abstract Recent studies have shown preliminary evidence for differentiation of the tumor microenvironment (TME) and immune landscape between molecularly-defined medulloblastoma (MB) subtypes. Identifying radiological correlates of these TME patterns could establish a non-invasive method of immune profile characterization for guiding patient-centered therapies. Here, we examine immune profiles between MB subtypes using data from Open Pediatric Brain Tumor Atlas (OpenPBTA), and their relationship to tumor measurements from pre-operative MRIs. We identified a retrospective cohort of 94 pediatric MB patients with available molecular subtyping and immune profiles (36 cell types) from bulk gene expression data. A random forest analysis was used to classify the four MB subtypes based on immune profiles. Four cell types had high impact on classification performance: plasmacytoid dendritic cells (PDC; 25.8% accuracy decrease when randomized), hematopoietic stem cells (HSC; 21.9%), plasma B cells (20.3%), and cancer associated fibroblasts (18.8%). Pairwise comparisons revealed SHH and WNT tumors had significantly higher numbers of fibroblasts and HSCs compared to Group3/Group4. We also found novel evidence for significantly lower amounts of plasma B cells in the SHH group, and high PDC levels in Group4, followed by Group3, and low PDC in SHH/WNT. Multi-parametric MRI scans for 39 patients were used to segment tumor volumes. Overall tumor volume was significantly correlated with composite stroma scores (R = 0.34, p = 0.036). Additionally, patients with higher volumes of gadolinium contrast-enhancing compared to non-enhancing components had higher immune (R = 0.42, p = 0.009) and microenvironment (summed immune and stromal cell types; R = 0.44, p = 0.006) scores, regardless of their molecular subtype. Together, our results demonstrate: (1) the use of rich immune profiles for differentiating molecular subtypes of MB and their unique TME characterization; and (2) initial evidence for radiological correlates of these profiles based on pre-operative imaging collected through standard practices.
EXTH-58. UNRAVELING THE MECHANISMS UNDERLYING THE THERAPEUTIC EFFICACY OF TIM-3 BLOCKADE IN DIPGS
Authors: Iker Ausejo-Mauleon, Sara Labiano, Virginia Laspidea, Daniel de la Nava, Javier Marco-Sanz, Antonio Tallón-Cobos, Oren Becher, Jiang Li, Mariella Filbin, Fernando Pastor, Marta M Alonso
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor and the leading cause of pediatric death caused by cancer. Despite great strides in the understanding of this disease, the survival is still dismal. One of the objectives of our lab is to modulate the tumor microenvironment (TME) towards a proinflammatory phenotype to render these tumors amenable to immunotherapy. TIM-3 is a member of the TIM-family of immunoregulatory proteins expressed on multiple immune cell types, including T-cells, NK, myeloid populations, and microglia, regulating adaptive and innate immunity. In silico assessment of TIM-3 expression in DIPG mRNA and single-cell datasets showed a robust expression of this gene in tumor cells and microglia uncovering this molecule as a potential target in DIPGs. In vivo studies showed that TIM-3 blockade with an antibody significantly increased the overall survival of two DIPG immunocompetent orthotopic models, led to long-term survivors (50%), and showed immune resident memory. TIM-3 inhibition resulted in a significant increase in the number and proliferative state of microglia, NK, and CD8+ cells and higher levels of IFNγ, GrzB and TNFα corresponding to NK and T-cell activate phenotypes. Interestingly, there was a decrease in the Treg population, which causes an increase in the pro-inflammatory CD8/Treg ratio. Chemokine studies demonstrated an augmentation of CCL5, CCL2 chemotactic cytokines, and CXCL10/IL-1β/IFN-γ pro-inflammatory axis in the tumor microenvironment of treated-mice. Additionally, DCs, CD4+, and CD8+ cells were increased in treated draining lymph nodes and of functional significance, expressed higher amounts of pro-inflammatory cytokines than in control mice. Interestingly, the depletion of the different immune populations did not completely abrogate the treatment efficacy indicating a residual although significant TIM-3 effect in the tumor. In conclusion, these data uncover TIM-3 as a potential target for the treatment of DIPG and its potential as an immune regulator of DIPG TME.
EXTH-33. PRIMING OF SYNNOTCH CAR T CELLS VIA CNS-SPECIFIC ANTIGEN ALLOWS SPATIAL AND TEMPORAL REGULATION OF CAR EXPRESSION, EFFECTIVE HOMING AND PERSISTENCE OF T CELLS IN THE CNS
Authors: Payal Watchmaker, Milos Simic, David Diebold, Psalm Pineo-Cavanaugh, Jason Deucker, Wei Yu, Wendell Lim, Hideho Okada
Journal: Neuro-Oncology (2022)

Abstract One of the key challenges in the development of CAR-T therapy is the absence of target antigens that are tumor-specific and have homogenous expression. To safely target glioblastoma-associated antigens (GAAs) in the tumor without attacking normal tissue expressing the same GAAs outside of the brain, we adapted a novel synthetic Notch (synNotch) receptor system and established a “prime and kill” sequential two-receptor CAR circuit. We used glioblastoma- (GBM) specific neoantigen EGFRvIII as a priming signal for synNotch receptor and have reported robust antitumor response in the mice bearing intracerebral PDX tumor with heterogenous EGFRvIII expression. However, less than 20% of adult GBM cases express EGFRvIII. Furthermore, EGFRvIII expression can diminish over time even after its detection in the primary GBM, and the EGFRvIII-synNotch primed CAR T cells may deplete EGFRvIII-expressing GBM cells via their cytotoxic effects, thereby losing the priming signal. To overcome these inherent challenges of the EGFRvIII-priming strategy, we used CNS tissue-specific antigens as priming signal to drive localized expression of the CAR against EphA2 and IL-13Rα2 and bypassed the need for tumor-specific antigen. We have found BCAN (also known as Brevican) as the most promising priming antigen among several CNS-specific cell surface proteins that we evaluated. When mice bearing intracerebral GBM6 PDX received a single IV infusion of T cells engineered with the α-BCANsynNotch- &amp;gt; α-EphA2/IL-13Rα2 CAR (B-SYNC) circuit, all mice (10/10) demonstrated complete regression of the tumor. Furthermore, these B-SYNC T cells were significantly more efficacious than constitutively expressed EphA2/IL-13Rα2 CAR T cells, associated with superior persistence and less exhausted phenotype. Thus, the B-SYNC approach represents a conceptual novelty of CNS tissue-specific CAR activation. This also enhances the translational significance of synNotch-CAR T cells by widely extending the eligibility to EGFRvIII-negative glioma patients. We will develop and conduct a phase I study to evaluate our hypothesis.
SURG-32. A NOVEL MACHINE LEARNING APPROACH FOR MODELING THE PREDICTIVE VALUE OF COMORBIDITY INDICES IN PITUITARY SURGERY
Authors: Shane Shahrestani, Nolan Brown, Julian Gendreau, Joshua Bakhsheshian, Ben Strickland, Jacob Ruzevick, John Carmichael, Gabriel Zada
Journal: Neuro-Oncology (2022)

Abstract Although pituitary adenomas (PAs) are common intracranial tumors, literature evaluating the utility of comorbidity indices for predicting perioperative complications in patients undergoing pituitary surgery remains limited, thereby hindering the development of complex models that aim to identify high-risk patient populations. Accordingly, we utilized comparative modeling strategies to evaluate the predictive validity of various comorbidity indices and combinations thereof in predicting key pituitary surgery outcomes. The Nationwide Readmissions Database was used to identify patients who underwent transsphenoidal pituitary tumor operations (n=19,653) in 2016-2017. Patient frailty was assessed using the Johns Hopkins Adjusted Clinical Groups (JHACG). Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI) were calculated for each patient. Five sets of generalized linear mixed-effects models were developed, using 1) Frailty, 2) CCI, 3) ECI, 4) Frailty+CCI, or 5) Frailty+ECI as the primary predictor. Complications investigated included inpatient mortality, non-routine discharge (e.g., to locations other than home) , length of stay (LOS) within the top quartile, cost within the top quartile, and one-year readmission rates. Postoperative mortality occurred in 73 patients (0.4%), one year readmission was reported in 2,994 patients (15.2%),and non-routine discharge occurred in 2,176 (11.1%) patients. The mean adjusted all-payer cost for the procedure was $25,553.85±$26,518.91 (Top Quartile: $28,261.20) and mean LOS was 4.8 days±7.4 days (Top Quartile: 5.0 days). The model using frailty+ECI as the primary predictor consistently outperformed other models, with statistically significant p-values as determined by comparing their AUCs, for most complications. For prediction of mortality, however the Frailty+ECI model (AUC:0.831) was not better than the ECI model alone (AUC:0.831;p=0.95). For prediction of readmission the Frailty+ECI model (AUC:0.617) was not better than the frailty model alone (AUC:0.606;p=0.10) or the Frailty+CCI model (AUC:0.610;p=0.29). Knowledge gained from these models may help neurosurgeons identify high-risk patients requiring additional clinical attention or specific resource utilization prior to surgical planning.
SURG-19. PROGNOSTIC VALIDATION OF A NEW CLASSIFICATION SYSTEM FOR EXTENT OF RESECTION IN GLIOBLASTOMA: A REPORT OF THE RANO RESECT GROUP
Authors: Philipp Karschnia, Jacob S Young, Antonio Dono, Levin Häni, Tommaso Sciortino, Francesco Bruno, Stephanie T Jünger, Nico Teske, Ramin A Morshed, Alexander F Haddad, Yalan Zhang, Sophia Stöcklein, Michael Weller, Michael Vogelbaum, Juergen Beck, Nitin Tandon, Shawn L Hervey-Jumper, Annette Molinaro, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Mitchel S Berger, Susan M Chang, Martin van den Bent, Joerg-Christian Tonn
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (I) explore the prognostic utility of the classification system and (II) define how much removed non-CE tumor translates into a survival benefit. METHODS The international RANO resect group retrospectively searched the databases from seven neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and post-operative MRI were collected. RESULTS We collected 1021 patients with newly diagnosed glioblastoma, including 1008 IDHwt patients. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC 26981/22981 (TMZ/RT→TMZ) following surgery. Among such homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with ‘maximal CE resection’ (class 2) had superior outcome compared to patients with ‘submaximal CE resection’ (class 3) or ‘biopsy’ (class 4) (median OS: 19 versus 15 versus 10 months; p=0.001). Extensive resection of non-CE tumor (≤ 5 cm3 residual non-CE tumor) provided an additional survival benefit in patients with complete CE resection, thus defining class 1 (‘supramaximal CE resection’) (median OS: 24 versus 19 months; p=0.008). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers including MGMT promotor status. Relative tumor reduction (in percentage) was not prognostic for outcome on multivariate analysis, and inter-rater agreement for CE and non-CE tumor on post-operative MRI was sufficient. CONCLUSION The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification of clinical trials. Removal of non-CE tumor beyond the CE tumor borders translates into additional survival benefit, providing a rationale to explicitly denominate such a ‘supramaximal CE resection’.
STEM-06. NUCLEAR STRUCTURE MAINTAINS GLIOBLASTOMA STEM CELLS
Authors: Tingting Duan, Shruti Bhargava, Jeremy Rich
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma stem cells (GSCs) contribute to therapeutic resistance, promote tumor angiogenesis, and evade anti-tumor immune responses. We and others have shown that GSCs display differential regulation of their epigenetic landscapes and metabolic profiles and contribute to the striking cellular heterogeneity and complex tumor microenvironments. Here, we find that GSCs undergo dramatic changes in chromatin organization and nuclear morphology upon differentiation. Leveraging unbiased RNA sequencing and protein profiling screens comparing GSCs and differentiated glioma cells, we identified nuclear membrane molecular regulation that defines nuclear size and lipid regulation. Genetic or pharmacologic targeting of nuclear envelope function reduced cancer stem cell proliferation, self-renewal, and in vivo tumor growth. Collectively, we define a novel role of the nuclear envelope in maintaining chromatin state and cancer stem cell self-renewing, informing the development of novel potential therapeutic paradigms for glioblastoma.
MODL-27. PRECLINICAL INTERROGATION OF IMMUNOTHERAPY TREATMENT STRATEGIES IN GLIOBLASTOMA (GBM) USING A CLINICALLY RELEVANT DISEASE MODEL
Authors: James Clerkin, Kate Connor, Kieron White, Kieron Sweeney, Liam Shiels, Thomas Van Brussel, Ingrid Arijs, Diether Lambrechts, Stephen Maher, Laure Marignol, Jochen Prehn, David O'Brien, Annette Byrne
Journal: Neuro-Oncology (2022)

Abstract Clinically faithful pre-clinical models are essential for screening therapies and studying resistance mechanisms. Historically models have failed to predict response in the clinical setting. Current models seldom incorporate surgical resection, and commonly use young animals whose immune contexture differs from older patients. Here, we have established an orthotopic model, employing the syngeneic, mesenchymal-NFpp10a-cell line, in both young and aged mice. We have characterised the model's response to standard of care resection and temozolomide (TMZ) treatment. We have further studied response to anti-PD1 therapy (adjuvant and neoadjuvant). NFpp10a-Luc2 expressing cells were orthotopically implanted into C57BL/6 mice (aged { &amp;gt; 18months} and young {6-8weeks}) and weekly bioluminescence imaging (BLI) performed to monitor tumour growth. Several therapeutic interventions were assessed to study tumour growth and survival: (1)surgical resection, (2)TMZ, (3)anti-PD1 (4)neoadjuvant anti-PD1. RNAseq, murine microenvironment cell population (mMCP) counter and gene ontology analyses characterised treatment related changed in the TME. We demonstrated survival advantage in aged mice undergoing resection (Resection:33.5 days vs Non-Resection:18 days;p=0.0166). Subsequently, we observed that TMZ and anti-PD1 monotherapy had no impact on NFpp10a-Luc2 growth (TMZ-overall:p=0.9001, and anti-PD1-overall:p = 0.7933) or survival (TMZ-overall:p = 0.3035, anti-PD1-overall:p= 0.6328). Neoadjuvant anti-PD1 treated mice demonstrated no survival advantage compared to IgG control (33-days vs 35-days:p = 0.9429). or BLI signal (p = 0.1703). NFpp10a-Luc2 forms immune-cold TME relative to commonly employed models. mMCP counter analysis demonstrates neoadjuvant anti-PD1 induced influx of CD8+-T cells, B cells, and monocytes into the TME compared to IgG control, and was associated with significantly upregulated CXCR3 chemokine receptor binding pathway on gene ontology analysis (p = 0.0045). Overall, we have, for the first time established and characterised response of the NFpp10a-Luc2-C57BL/6 model to resection, TMZ and anti-PD1 therapies. NFpp10a-Luc2 tumours demonstrate similar therapeutic resistance and TME profile compared to human mesenchymal GBM. The model may therefore be employed in future pre-clinical studies to guide clinical trials in mesenchymal GBM.
NIMG-80. A RADIOMICS-BASED MODEL PREDICTIVE OF OVERALL SURVIVAL IN GLIOBLASTOMA USING MULTI-INSTITUTIONAL PREOPERATIVE MRI SCANS
Authors: Roman Kowalchuk, Gian Marco Conte, David Crompton, Ricardo Domingo Cabreja, Carlos Perez Vega, Mana Moassefi, Shahriar Faghani, Bardia Khosravi, Sujay Vora, Bradley Erickson, Daniel Trifiletti
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Though patients with glioblastoma generally have poor overall survival (OS), OS estimates range significantly. We sought to develop a radiomics-based model predictive of OS in glioblastoma using preoperative MRI scans to identify these differences and guide clinical care. METHODS The primary endpoint was OS, determined from the date of surgery to death or last follow-up. T1, FLAIR, T2, and post-contrast T1 (T1c) MRI sequences were obtained for all patients. Using HD-GLIO-AUTO, lesion segmentation yielded three masks corresponding to the regions of contrast enhancement, non-enhancement, and total volume. Radiomics features were extracted from each region from the T2 and T1c sequences independently (i.e. either from T2 or T1c) and in combination. Age at surgery and gender were also considered. The data was split into training (75%) and test (25%) sets, stratifying for age at surgery. Kaplan-Meier analysis and the Coxnet model were used. For Coxnet, Elastic Net was used as the penalty, with optimization of the L1 coefficient using 5-fold cross-validation and evaluation via the concordance index (C-index). RESULTS From 3 institutions, 383 patients were included. Median OS was 395 days: 346 patients died, and 37 were right-censored. Age &amp;gt; 65 years was predictive of decreased OS (p &amp;lt; 0.005), but gender was not (p=0.16). For the Coxnet model, the C-index was 0.67 (standard deviation: 0.01) considering T2 and T1c sequences for the total lesion volume, with a C-index of 0.65 for the test set. For the enhancing volume, the model had a C-index of 0.71 for the test set using T1c sequences. Overall, C-indices ranged from 0.62-0.71. CONCLUSIONS We present a novel radiomics-based model predictive of OS in glioblastoma across a multi-institutional dataset. Ongoing efforts will incorporate immediate postoperative imaging and IDH and MGMT status into the proposed model to further improve prognostic ability and help guide clinical decision-making.
EXTH-92. TARGETING PRIMARY CENTRAL NERVOUS SYSTEM B CELL LYMPHOMA IGH CLONOTYPES USING NOVEL RNA-NPS
Authors: Elizabeth Ogando-Rivas, Christina Von Roemeling, Paul Castillo, Ruixuan Liu, Hector Mendez-Gomez, Nagheme Thomas, Frances Weidert, Jonathan Chardon-Robles, Sadeem Qdaisat, Matthew Cascio, John Ligon, Jianping Huang, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Recurrent PCNSBLs represent a therapeutic challenge. Up to 60% of PCNSBL patients relapse to later face survival rates as low as 22%. Unfortunately, tumor heterogeneity and off-target effects have limited the success of immunotherapy against PCNSBL. METHODS We propose a novel immunotherapy to overcome PCNSBL heterogeneity and off-target effects in an exquisitely tumor specific manner using nanoparticle vaccination, capable of delivering personalized tumor derived mRNAs, that induces systemic orchestration of innate and adaptive immunity. We target tumor antigens derived from the B cell receptor (i.e., heavy chain immunoglobulin - IgH) clonotypes. IgH clonotypes are hypervariable gene rearrangements clonally generated by B cells. Tumor IgH clonotypes are unique for each malignant B cell clone and hence attractive immune targets, not shared by normal B cell clones avoiding undesirable off-target effects. RESULTS RNA-NPs can reprogram tumor microenvironment while activating the innate immunity via IFN type I (i.e., IFNα) and priming of hypervariable region clonotype specific T cell responses in naïve mice. We determined the rearranged IgH sequences (predominant clone 99% and nine additional clones with frequencies &amp;lt; 1%) of clinically relevant inbred murine PCNSBL models (BAL17 and A20) by PCR. The number of identified clonotypes confirmed the IgH variability observed in human B cell hematological malignancies. In preliminary experiments targeting lymphoma derived single clonotypes with RNA-NPs, we showed the feasibility of priming in-vivo T cells specific against hypervariable regions after 3 weekly i.v. RNA-NPs (median IFNγ: 58 pg/ml; range: 50-70 pg/ml vs controls &amp;lt; 30 pg/ml; p=0.008). Targeting of clonotype RNA-NPs was associated with decreased tumor growth (p=0.04). Interestingly, we have observed tumor reactive lymphangiogenesis that communicates with regional skull bone marrow observed in 3D microscopy that might direct future routes of RNA-NP administration. CONCLUSION Our RNA-NP systemic vaccination platform can induce PCNSBL clonotype specific T cell responses, sparing normal tissues.